DECLARE-TIMI 58 - Dapagliflozin & CV events in type 2 diabetes

Wiviott SD, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. NEJM

Bottom line: In patients with type 2 diabetes with existing ASCVD or with multiple CV risk factors, dapagliflozin did not reduce the risk of a composite of major adverse cardiovascular events; however, it did reduce the risk of HF hospitalizations (NNT 125) at 4.2 years. Dapaglifozin increases the risk of fungal genital infections (NNH 125) & DKA (NNH 500).

Overall assessment of the evidence for SGLT2 inhibitors shows several differences between agents in this class; empagliflozin appears to have the greatest potential for benefit, whereas canagliflozin has the highest potential for harm.

Context: Summaries of EMPA-REG with empagliflozin & CANVAS with canagliflozin

Patients (n=17,160)

  • Included

    • T2DM with HbA1c 6.5%-12.0%

    • + CrCl 60+ mL/min

    • + either

      • Established atherosclerotic cardiovascular disease (ASCVD; IHD, ischemic CVA, PAD) & 40+ y/o

      • Multiple risk factors: Male 55+ y/o or female 60+ y/o + tobacco use, HTN, or LDL >3.3 mmol/L

  • Key exclusion criteria:

    • Adherence <80% during run-in or considered “at risk for poor medication adherence”

    • Previous SGLT2 inhibitor use

    • Steroid use with equivalent of prednisone 10+ mg/d

    • ACS, decompensated HF or stroke within 8 weeks

    • BP >180/100

    • Recurrent UTIs

  • Baseline characteristics:

    • 64 y/o, male (63%), white (80%), North American (32%)

    • ASCVD (41%): CAD (33%), PAD (6%), CVA (8%)

    • HF (10%)

    • Diabetes duration median 11 y,

    • HbA1c median 8.3%

    • BP 135/85

    • eGFR 85 (7% with eGFR <60)

    • Meds

      • Antihyperglycemics: Metformin (82%), sulfonylurea (43%), insulin (41%), DPP-4i (17%), GLP1 agonist (4%)

      • ASA (61%), ACEI/ARB (81%), beta-blocker (53%), statin or ezetimibe (75%), diuretic (41%)

Intervention & control

  • I: Dapagliflozin 10 mg once daily

  • C: Matching placebo

  • Co-interventions: Other antihyperglycemics per standard of care, excluding SGTL2i or glitazones

Results @ median 4.2 years

Efficacy

  • No reduction in major adverse cardiovascular events (composite of CV death, MI or ischemic stroke): Dapagliflozin 8.8% vs placebo 9.4%

    • Hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.84-1.03

    • CV death: 2.9% in both groups

    • MI: 4.6% vs 5.1% (HR 0.89, 95% CI 0.77-1.01)

    • Ischemic stroke: 2.7% in both groups

  • Reduction in composite of CV death or HF hospitalization: 4.9% vs 5.8%

    • HR 0.83 (95% CI 0.73-0.95)

    • Driven by a reduction in HF hospitalization: 2.5% vs 3.3% (NNT 125, HR 0.73, 95% CI 0.61-0.88)

    • Originally a secondary outcome; switched to co-primary outcome before unblinding of outcomes due to favorable results on this outcome in EMPA-REG & CANVAS.

  • No reduction in death: 6.2% vs 6.6% (HR 0.93, 95% CI 0.82-1.04)

Safety

  • Increased:

    • Diabetic ketoacidosis (DKA): 0.3% vs 0.1% (NNH 500; HR 2.18, 95% CI 1.10-4.30)

    • Genital infection (generally fungal): 0.9% vs 0.1% (NNH 125)

  • Reduced:

    • Serious adverse events: 34.1% vs 36.2% (HR 0.91, 95% CI 0.87-0.96)

  • No difference in

    • D/C due to adverse event: 8.1% vs 6.9% (HR 1.15, 95% CI 1.03-1.28)

    • Amputation: 1.4% vs 1.3%

    • Symptomatic volume depletion: 2.5% vs 2.4%

    • UTI: 1.5% vs 1.6%

Effect on surrogate endpoints:

  • HbA1c -0.4%

  • Wt -1.8 kg

  • SBP/DBP -2.7/-0.7

Internal validity

  • Low risk of allocation, performance, detection & attrition bias

    • Computer-generated block-randomization sequence;

    • Centralized randomization by interactive voice/web response system to blinded kit containing intervention or matching placebo;

    • Low loss-to-follow-up (0.3%);

    • Analyzed by intention-to-treat.

  • Single-blind (patient) placebo run-in phase lasting 4-8 weeks to assess for non-adherence

    • Unclear risk of selection bias: 25,698 entered run-in phase -> 17,160 randomized (i.e. high rate of exclusion during placebo run-in)

Other Evidence

  • A meta-analysis of the 3 major CV outcome trials of SGLT2 inhibitors (CANVAS, DECLARE & EMPA-REG) shows the following overall patterns:

    • CV efficacy

      • Only empagliflozin clearly reduces all-cause & CV mortality (in patients with existing ASCVD, RRR 32%);

      • SGLT2 inhibitors reduce the risk of major adverse CV events (composite of CV death/MI/stroke) in patients with existing ASCVD (RRR 14%), but not in those without ASCVD;

      • SGLT2 inhibitors do not reduce/increase stroke;

      • All SGLT2 inhibitors reduce the risk of HF hospitalization (RRR ~30%), regardless of prior ASCVD or HF.

    • Safety

      • All SGLT2 inhibitors increase the risk of DKA (RR increase by 120%);

      • Only canagliflozin increases the risk of amputations (RR increase 26%) & fractures (RR increase by 11%).

EMPA-REG - Empagliflozin for CV risk reduction in T2DM with hx of CVD

Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

Bottom line: In patients with T2DM and CVD, empagliflozin (at either dose of 10 mg or 25 mg daily) reduced the risk of death (NNT 39) & CV events (NNT 63) over 3 years.

 

    Patients

    • Inclusion
      • Adults with T2DM
        • No glucose-lowering agents in previous 12 weeks: 7-9%
        • Receiving glucose-lowering agents, stable x12 weeks: 7-10%
      • Established CVD, defined as any of the following:
        • MI >2 months ago
        • CAD (confirmed with angiography)
        • Stroke >2 months ago
        • PAD documented by
          • Limb revascularization or amputation
          • Peripheral artery stenosis >50% on angiography or non-invasive evaluation
          • ABI <0.9 on at least 1 side
    • Key exclusion criteria
      • Cancer within last 5 y
      • Stroke/TIA within 2 months
      • Planned cardiac surgery or PCI in next 3 months
      • BMI >45
      • Blood dyscrasias or any disorder causing hemolysis or unstable RBCs
      • eGFR <30 mL/min/1.73 m^2
      • ALT, AST or ALP >3x ULN
    • 11,531 individuals screened across 590 sites in 42 countries -> 7028 randomized -> 7020 analyzed
    • "Average" patient
      • Age 63 y
      • Male 72%
      • White 72%, Asian 22%, Black 5%, other 1%
      • Geography: Europe 41%, North America 20%, Asian 19%, Latin America 15%, Africa 4%
      • CV risk factors
        • CAD 76% (multivessel 47%)
        • MI 46%
        • CABG 24%
        • Stroke 24%
        • PAD 20%
      • Time since T2DM dx: >10 y (57%), 5-10 y (25%), 1-5 y (16%)
      • Wt 87 kg, BMI 31
      • BP 136/77
      • Lipids: total 4.2, LDL 2.2, HDL 1.1 mmol/L
      • A1c 8%
      • Meds
        • Metformin 74%
        • Insulin 49%
        • Sulfonylurea 43%
        • DPP-4 inhibitor 11%
        • Antihypertensives 95%
          • ACEI 80%
          • Beta-blocker 64%
        • ASA 83%
        • Statin 76%

    Interventions & co-interventions (median 2.6 y)

    • I: Empagliflozin 10 mg or 25 mg
      • A1c lowered by 0.5-0.6% at 12 weeks vs placebo
    • C: Matching placebo
    • Co-interventions:
      • 1st 12 weeks after randomization: No change to glycemic management unles fasting glucose >13.3 mmol/L
      • After 12 weeks: Adjustment to glucose-lowering therapy according to local guidelines

    Results @ median 3.1 y

    • Results for both doses of empaglifozin were similar, and therefore pooled
    • Statistically significant reduction in:
      • The primary outcome (CV death, MI, stroke): Hazard ratio (HR) 0.86, 95% confidence interval 0.74-0.99 (p=0.04)
        • 10.5% vs 12.1% (NNT 63)
      • Death: HR 0.68 (0.57-0.82)
        • 5.7% vs 8.3% (NNT 39)
      • HF hospitalization: HR 0.65 (0.50-0.85)
        • 2.7% vs 4.1% (NNT 72)
    • No statistically significant difference:
      • MI: HR 0.87 (0.70-1.09) - 4.8% vs 5.4%
      • Stroke: HR 1.18 (0.89-1.56) - 3.5% vs 3.0%
      • Coronary revascularization: HR 0.86 (0.72-1.04) - 7.0% vs 8.0%
    • Safety
      • Serious adverse events: 38.2% vs 42.3% (NNT 25, p<0.001)
      • Premature discontinuation: 23.4% vs 29.3%
      • Hypovolemia: 5.1% vs 4.9%
      • Acute kidney injury: 1.0% vs 1.6%
      • UTI: 18.0% vs 18.1% (complicated 1.7% vs 1.8%)
      • Genital infection: 6.4% vs 1.8% (NNH 22)
      • DKA: 0.1% vs <0.1%
      • Hypoglycemia (glucose <3.9 mmol/L or requiring assistance): 27.8% vs 27.9%
    • Numerous subgroup analyses were performed, which demonstrated inconsistent subgroup interactions with the primary outcome and CV death

    Issues with internal validity?

    • No: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up (<0.1%) analyzed using intention-to-treat principles 
    • Run-in: 2-week open-label placebo run-in

    Additional considerations

    • The reduction of CV events became apparent after only 3 months. Previous trials of diabetes drugs or glycemic control goals have never demonstrated a benefit this early, suggesting that the apparent benefit of empagliflozin may have resulted from another mechanism. 
    • The reduction int the primary CV event resulted mainly from a reduction in CV death, but not MI or stroke. This further argues against glycemic control as the beneficial mechanism of empagliflozin.